Age-related macular degeneration (AMD) affects some 10 million people in the United States. Blindness in AMD occurs due to either choroidal neovascularization (CNV) or geographic atrophy (GA). Whereas new treatments for CNV offer the prospect of vision improvement, the nebulous understanding of GA pathogenesis has precluded the arrival of any FDA-approved therapy for the nearly 1 million Americans that have GA. In a multi-center collaboration, we recently reported that a hypomorphic polymorphism in toll-like receptor-3 (TLR3), an innate immune sensor of double stranded RNA (dsRNA), conferred protection from GA, making it the first candidate gene specific for GA. We showed that TLR3 activation by long dsRNA induced apoptotic cell death of primary human retinal pigmented epithelium (RPE) cells and choroidal endothelial cells (CECs) and retinal degeneration in mice resembling GA, thereby establishing a functional link between TLR3 and GA. New and exciting recent work from my laboratory revealed the presence of non-physiological long dsRNA in the eyes of patients with GA but not in human eyes without AMD. Thus we hypothesize that TLR3 activation by long dsRNA triggers retinal and choroidal cell death and promotes GA. Using molecular modeling we discovered a novel class of ultrashort (us)-dsRNAs that function as TLR3 inhibitors in vivo. The objective of this proposal is to identify the optimal us-dsRNA molecules that can rescue TLR3-mediated retinal degeneration to achieve our long-term goal of advancing them as therapeutics for GA. These proof-of-concept studies will form the basis for an R01 application that will define the detailed mechanisms of action of long dsRNA and us-dsRNA. Successful completion of this project also will have the high translational impact of laying the foundation for a collaborative clinical trial for GA, which is presently an unmet medical need. PUBLIC HEALTH RELEVANCE: Geographic atrophy is responsible for 10% of blindness due to age-related macular degeneration (AMD). There is no FDA-approved therapy for the 1 million Americans with GA. Our recent discovery of TLR3 as the first gene specifically associated with GA and our exciting new finding that double stranded RNA (dsRNA), which activates TLR3, is present in human eyes with GA support the pursuit of a novel class of TLR3 inhibitors that we have discovered as potential therapeutics for this unmet medical need.